Overcoming BTKi Resistance in CLL with the Dual-Action 4th Generation Inhibitor LP-168

Chronic lymphocytic leukemia (CLL) treatment has seen advancements with targeted therapies, specifically Bruton's tyrosine kinase (BTK) inhibitors. However, the emergence of resistance mutations, such as C481S, T474I, and L528W, poses challenges. LP-168 is a novel, ultra-selective fourth-generation BTK inhibitor designed to address these resistance issues with both covalent and non-covalent binding capabilities.

In a comprehensive kinase assay, LP-168 showed high selectivity for BTK, with significant potency against both wildtype and C481S BTK mutants. The compound effectively inhibited BCR signaling and reduced the migration capacity of primary CLL cells in a time-dependent manner. LP-168 also demonstrated cytotoxicity against primary CLL cells, both in isolation and in co-culture with HS-5 stromal cells, with efficacy comparable to or better than existing BTK inhibitors.

Furthermore, LP-168 significantly decreased the production of chemokines CCL3 and CCL4 by CLL cells. It showed cytotoxic effects on CLL cells with resistance mutations C481S and T474I, as well as reduced chemokine production in these cells. The in vivo efficacy of LP-168 was assessed using mouse engraftment models, where it significantly improved survival compared to vehicle and ibrutinib.

In conclusion, LP-168 has proven to be a potent and selective BTK inhibitor with activity against CLL, including cases with resistance-conferring mutations. The compound's in vivo efficacy and selectivity support its ongoing preclinical and clinical investigation for the treatment of CLL and NHL.